Abstract 2863: RNase-L modulates the immune response to intestinal damage and ameliorates murine colitis and colitis-associated cancer.

Abstract

The endoribonuclease RNase-L is a Type-I interferon (IFN)-regulated component of the innate immune response that functions in antiviral and antibacterial activities. Here we identify a protective role for RNase-L in the inflammatory response to gastrointestinal (GI) injury and commensal bacteria. In a dextran sulphate sodium (DSS)-induced model of ulcerative colitis RNase-L-/- mice exhibited a more severe clinical score and increased mortality compared to wild type animals. The enhanced sensitivity to GI damage was accompanied by delayed leukocyte infiltration and reduced expression of the proinflammatory cytokines IFNβ, TNFα, IL-1β and IL-18 at early times post-DSS exposure. This impaired innate immune response corresponded with increased inflammation and a decreased capacity to recover from GI injury at later times. Consistent with the established role of inflammation as a risk factor for colorectal cancer, in a model of colitis-associated cancer DSS treated RNase-L-/- mice displayed an increased carcinogen-induced tumor burden and mortality. A potential mechanism by which RNase-L functions in the response to GI damage and commensal bacteria is via the production of RNA agonists of RIG-I-like receptors (RLRs), sensors of cytosolic pathogen-associated RNAs that initiate signaling to induce proinflammatory cytokines important to GI homeostasis. Indeed, we found that bacterial RNA triggers IFNβ induction in macrophages in an RNase-L-dependent manner. Together, these results support a model in which the protective role for RNase-L in experimental colitis and colitis-associated cancer occurs through RNase-L-dependent RLR signaling and IFNβ induction. Citation Format: Tiha M. Long, Arindam Chakrabarti, Heather Ezelle, Sarah Brennan-Laun, Jean-Pierre Raufman, Irina Polyakova, Robert Silverman, Bret Hassel. RNase-L modulates the immune response to intestinal damage and ameliorates murine colitis and colitis-associated cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2863. doi:10.1158/1538-7445.AM2013-2863